The primary transmission mode of HIV is genital-to-genital contact, blood, sperm, and blood transfusion. This virus attacks the body’s immune system, leading to acquired immunodeficiency syndrome (AIDS), a condition in which the immune system gradually fails, allowing dangerous opportunistic infections and cancer to develop. HIV primarily infects cluster of differentiation 4⁺ (CD4⁺) T cells, dendritic cells, and macrophages ^[1][22].

Furthermore, the condition may reduce the number of CD4⁺ T cells to a critical level, resulting in a loss of cell-mediated immunity and greater susceptibility to opportunistic infection, eventually leading to AIDS ^[2][23]. As of 2019, the World Health Organization (WHO) estimates that 38 billion people worldwide are infected with HIV ^[3][24]. However, approximately 1.7 million people were unaware they were HIV-positive ^[3][24]. Therefore, several antiretroviral drugs that may slow the progression of HIV in the body have been discovered and developed. Antiretroviral drugs were only recently available to 67% of the world’s population. Lopinavir, darunavir, atazanavir, and saquinavir are protease inhibitors, while lamivudine, stavudine, emtricitabine, efavirenz, nevirapine, and rand aziridine are reverse transcription inhibitors ^[4][7]. However, no HIV drug on the market can cure HIV.

Natural products produced by microorganisms, as shown in Table 1, could be used to develop anti-HIV medications. Anti-HIV bioactive compounds from fungi are widely considered to be one of the most promising sources. Several compounds, including alachalasin A from Podospora vesticola fungus cultures, have been identified as effective HIV-1 replication suppressors in cellosaurus cells C8166 ^[5][6][25,26]. The half-maximal effective concentration, or EC₅₀, of alachalasin is 8.01 μM. Pestalofone A, as well as its derivatives, including pestalofone B and E, as well as pestaloficiol G, H, J, and K isolated from the Pestalotiopsis fici fungus, possess anti-HIV activity ^[7][8][27,28]. Furthermore, epicoccin G and H were isolated from ascomycete Epicoccum nigrum fermentation culture, in addition to its diphenylalazine A ^[9][29]. Another study discovered that bacillamide B, derived from the ascomycete Tricladium sp., exhibited anti-HIV activity ^[10][30]. Furthermore, cytochalasan alkaloids, such as armochaetoglobin K, L, M, N, O, P, Q, and R, purified from the arthropod-associated Chaetomium globosum fungus had significant anti-HIV activity (EC₅₀ = 0.25–0.55 μM) ^[11][31].

An ocean-dwelling fungus is one of the most potent sources of HIV-combating compounds. Meroterpenoids with a phenylspirodrimane skeleton, such as stachybotrin D, derived from the sponge-derived fungus Stachybotrys chartarum MXH-X73, were able to inhibit HIV-1 replication by targeting the reverse transcriptase enzyme ^[13][32]. This fungus was discovered on the island of Xisha in China, where it was isolated from the marine sponge Xestospongia testudinaris ^[13][32]. Furthermore, stachybotrysams A, B, and C, extracted from a different strain of Stachybotrys chartarum, also showed strong HIV-inhibitory activity ^[14][33]. Another report showed that chartarutine B, G, and H, which are all derived from the sponge-associated Stachybotrys chartarum, have shown significant antiviral activity against the HIV-1 virus ^[15][34]. In addition, malformin C, derived from the marine fungus Aspergillus niger SCSIO Jcsw6F30, demonstrated significant anti-HIV-1 activity with an IC₅₀, a half-maximal inhibitory concentration, of 1.4 μM when tested on HIV-infected TZM-bl cells (also called JC.53bl-13) ^[16][35]. In addition, aspernigrin C from the same fungus also demonstrated similar action with an IC₅₀ of 4.7 μM ^[16][35].

An anti-HIV bioassay conducted in 293T cells, also refered as a highly transfectable derivative of human embryonic kidney 293 cells, revealed that eutypellazine E, extracted from a fungus found in the depths of the ocean named Eutypella sp., significantly inhibited HIV-1 proliferation ^[18][36]. Furthermore, unlike truncateol P, truncateol O, which is derived from the ascomycete Truncatella angustata, was found to inhibit the replication of both the H1N1 and HIV-1 viruses ^[19][37]. In addition, penicillixanthone A which is derived from the fungus Aspergillus fumigatus that is native to jellyfish, has been shown to possess significant anti-HIV-1 activity by inhibiting the infection of CXCR4-tropic HIV-1 NL4-3 and CCR5-tropic HIV-1 SF162 ^[20][38]. Additionally, the fungus Chaetomium globosum found in the depths of the ocean was able to produce 1,3-dihydro-4,5,6-trihydroxy-7-methylisobenzofuran, epicoccone B, and xylariol ^[21][39]. They showed highly effective anti-HIV activity in vitro at the concentration of 20 μg/mL, with 75.10, 88.4, and 70.20% suppression rates, respectively ^[21][39].

Endophytic fungus metabolites have been demonstrated to possess a vast array of bioactivities, including anti-HIV properties. Phomonaphthalenone A and bostrycoidin, both of which were derived from the endophytic fungus Phomopsis sp., showed moderate anti-HIV activity and low cytotoxicity, with IC₅₀ values of 11.6 and 9.4 μg/mL, respectively ^[22][40]. In addition, altertoxin I, II and III derived from the endophytic fungus Alternaria tenuissima QUE1Se inhibited HIV-1 virus replication completely ^[23][41]. The epoxyperylene structure of these molecules is a promising scaffold for the development of potent and non-toxic anti-HIV therapies ^[23][41]. Alternariol 5-O-methyl ether, on the other hand, was identified as a molecule that inhibits HIV-1 pre-integration processes after screening a library of bioactive compounds from the endophytic fungus Colletotrichum sp. ^[24][42]. Ergokonin A and B isolated from the endophytic fungus Trichoderma sp. Xy24 had IC₅₀ values of 1.9 μM, which indicated that it significantly suppressed the HIV-1 virus ^[25][43]. Recently, it was discovered that the endophytic fungus Phomopsis sp. CGMCC No. 5416 produces phomopsone B and C, and these two phomopsones have significant antiviral activity, with IC₅₀ values of 7.6 and 0.5 μmol/L, respectively ^[26][44]. Furthermore, the phenol pericochlorosin B, isolated from the endophytic fungus Periconia sp. F-31, showed significant anti-HIV activity in 293T cells, with an IC₅₀ value of 2.2 μM ^[27][45]. In 2017, Pang et al. discovered four compounds produced by the plant endophytic fungus Aspergillus sp. That belong to phenalenone derivatives ^[28][46]. These compounds include asperphenalenone A and D, cytochalasin Z₈, and epicocconigrone A, which have anti-HIV activities in vitro with IC₅₀ values of 4.5, 2.4, 9.2, and 6.6 μM, respectively ^[28][46]. The endophytic fungus was isolated from the Kadsura longipedunculata plant, also known as the Chinese Kadsura Vine, and used in traditional Chinese medicine ^[28][46]. Lamivudine and efavirenz, two control positives, demonstrated a greater activity level, with IC₅₀ values of 0.1 and 0.0004 μM, respectively ^[28][46].